A review of the most important natural antioxidants and effective medicinal plants in traditional medicine on prostate cancer and its disorders

Introduction The prostate gland, as age increases, may be affected by many diseases, including benign prostatic hyperplasia (BPH) and prostate cancer, due to impaired normal growth of the gland (1). Prostate cancer is a condition in which malignant cells originate in prostate tissues and irregularly proliferate, resulting in an increase in volume of each of the cellular components of the prostate gland (2,3). Prostate cancer is one of the most common cancers and the second leading cause of cancer deaths in men (4,5). Although prostate cancer is more common in older men, studies have shown that one third of men in the 30’s and 40’s have histological evidence of prostate adenocarcinoma (6). The formation of a tumor in the prostate is related to several factors such as age, race, diet, heredity, and the environment (7). In addition, inflammation is also a major contributor to prostate diseases and may play a role in the growth of tumor cells. Prostate cancer seems to be partly related to genetics, but environmental factors are also involved (8,9). Prostate diseases have adverse effects on fertility and also cause urinary problems due to the anatomical condition of the prostate (10,11). Prostatitis is classified as acute, chronic, asymptomatic inflammatory (chronic pelvic pain syndrome), and chronic bacterial. http://www.herbmedpharmacol.com doi: 10.34172/jhp.2020.15


Introduction
The prostate gland, as age increases, may be affected by many diseases, including benign prostatic hyperplasia (BPH) and prostate cancer, due to impaired normal growth of the gland (1). Prostate cancer is a condition in which malignant cells originate in prostate tissues and irregularly proliferate, resulting in an increase in volume of each of the cellular components of the prostate gland (2,3). Prostate cancer is one of the most common cancers and the second leading cause of cancer deaths in men (4,5). Although prostate cancer is more common in older men, studies have shown that one third of men in the 30's and 40's have histological evidence of prostate adenocarcinoma (6). The formation of a tumor in the prostate is related to several factors such as age, race, diet, heredity, and the environment (7). In addition, inflammation is also a major contributor to prostate diseases and may play a role in the growth of tumor cells. Prostate cancer seems to be partly related to genetics, but environmental factors are also involved (8,9). Prostate diseases have adverse effects on fertility and also cause urinary problems due to the anatomical condition of the prostate (10,11). Prostatitis is classified as acute, chronic, asymptomatic inflammatory (chronic pelvic pain syndrome), and chronic bacterial.
Prostatitis may develop at any ages (12,13). Several studies in different countries have confirmed the beneficial effects of herbal therapy on prostate cancer and other diseases (14). In developed countries, prostate cancer is the second leading cancer in men, so that one out of every six men develops the cancer (15). With the increasing prevalence of prostate cancer deaths and the inefficacy of chemotherapy and radiation therapy in advanced forms of this cancer, new methods are needed to control this cancer (16). BPH is the fourth leading disease in men over the age of 50 (17). As the age advances, the prevalence of BPH increases (18)(19)(20)(21)(22). Most of the plants' properties are related to antioxidant activity (23), which is mainly due to the presence of phenolic compounds (24). However, other compounds are likely to be involved in the plants' activities. Nettle is known to exhibit positive effect on the treatment of BPH (25). The main activity of nettle seems to be exerted by disrupting dihydrotestosterone binding to cytosol and nuclear receptors (26), explaining the role of the plant in preventing prostate cancer. A recent study showed that 20% extract of the nettle had specific antiproliferative effects on the epithelial and stromal cells of the prostate (27,28). There is a compound in the garlic that has been reported to inhibit the growth of prostate cancer cells in vitro. Garlic can counteract cancer causing agents. In garlic, the compound S-allyl cysteine has high antitumor properties, thus converting remaining testosterone products into low-risk materials (29)(30)(31). A review study has shown that Allium can effectively inhibit proliferation of the LNCaP prostate cancer cells (32). Green tea can have inhibitory effects on prostate cancer. Studies on rats have shown that green tea is able to inhibit the enzyme 5-alpha reductase. This enzyme is a conversion factor of testosterone to dihydrotestosterone, which is a carcinogenic agent in the prostate (33). Researchers have found that the strongest of these compounds in the green tea is epigallocatechin-3-gallate (34). Epigallocatechin-3-gallate and other green tea compounds inhibit the activity of an enzyme called proteasome. Proteasome is a key factor in the development of prostate cancer (35). Studies have shown that curcumin blocks the growth of the prostate cancer cell by inhibiting the activity of the enzyme tyrosine kinase in the epidermal growth factor receptor (36). One study demonstrated that curcumin is effective in treating androgen dependent prostate cancer (37). In a recent study, curcumin was observed to inhibit prostate cancer cells, and completed this action by blocking the effects of factors called AP-6 and NF-KappaB (38). A study on animal tissue reported evidence for the positive effect of the Pygeum africanum extract on inflammation involved in the development of BPH (39).
A clinical study has shown that P. africanum can improve enlarged prostate gland and prevent development of incidental prostate cancer (40)(41)(42). A study suggested that the therapeutic and preventive effects of hydroalcoholic extract of Thymus vulgaris on precancerous lesions and squamous cell carcinoma of the prostate gland observed in Wistar rats can be attributed to thymol and carvacrol. Flavonoids are other compounds in the hydroalcoholic extract of Thymus vulgaris which have anti-cancer effects (43). The aim of this study was to identify and report the most important medicinal plants that affect prostate disorder.

Materials and Methods
The information used in this review was obtained from the articles indexed in the databases Iran Medex, Irandoc, PubMed, Scopus, Web of Science, Scientific Information Database, Google Scholar, Magiran, etc. using the search terms prostate cancer, prostate inflammation and diseases, prostatitis, medicinal plants, medicinal plants effective on prostate cancer, medicinal plants effective on prostate inflammation and prostatitis, mechanism of action of medicinal plants effective on prostate cancer, and antioxidant and anticancer effects of extracts and essential oils of medicinal plants effective on prostate diseases. In this study, 165 articles were reviewed. After the initial review, 80 articles were found to address the subject of our review. Irrelevant articles were also excluded. Finally, 80 articles related to the purpose of our review published by 2019 were included in the final analysis.

Results
The medicinal plants and their natural antioxidants, which we examined in this study, effectively influence the treatment and prevention of prostate diseases and cancer and prostatitis via the potential mechanisms reported (Table 1). Based on the results of a review of numerous articles, some of the most important plants for the treatment and prevention of prostate cancer, and infections and inflammation of the prostate gland include Panax ginseng (Asian ginseng), Arum palaestinum (black calla), Melissa officinalis (common balm), Syzygium paniculatum (magenta cherry), Coptis chinensis (magenta lilly pilly), Embelia ribes (false black pepper), Scutellaria baicalensis (Baikal skullcap), Tripterygium wilfordii (thunder god vine), Salvia triloba (Greek sage), Ocimum tenuiflorum (holy basil), Psidium guajava (common guava), Ganoderma lucidum (mushroom ), Litchi chinensis (Lychee), Saussurea costus (costus), Andrographis paniculata (green chiretta), Magnolia officinalis (houpu magnolia) and Prunus Africana (African cherry). The supplementary information and detailed therapeutic action mechanisms of medicinal plants are shown in Table 1.

Scientific name Family name Part of plant Common name Study model The mechanisms of antioxidant and anticancer actions of the most important medicinal plants effective on prostate diseases and prostate cancer Ref.
Panax ginseng Araliaceae Root Ginseng Rat The group treated with P. ginseng showed significantly lesser prostate size and weight than the testosterone-induced BPH group. In addition, P. ginseng decreased the mRNA expression of Adra1d as well as the expression of EGFR and BCL2 in prostate tissue. Arum The aqueous extract of the root and leaf of this plant is used at a dose of 1000 mg/kg body weight and activates caspase 6 and suppresses the tumor. This caspase is an important marker for prostate cancer.
Androsace Primulaceae Aerial part rockjasmine Rat The flavonoids isolated from this plant, oleanane-type triterpene saponin, increase cytotoxicity and alter the morphology of the cell as well as the sub-G0/G1 phase, leading to an increase in apoptosis in prostate cancer cells and other cancerous tissues. It also induces the death of autophagy of the cell by converting LC3B-I to LC3B-II and producing autophagy vaccines. Flavonoids in this plant also inhibit PI3k, Akt, mTOR, and inhibit migration and invasion of cells.    The methanolic extract of this plant, including triterpenoids, flavonoids, essential oil, and tannins, suppresses PI3K/AKT/mTOR/S6K1 and mitogen-activated protein kinases (MAPKs), also lowers the levels of proteins involved in cell proliferation, Anti-apoptotic and metastatic, at a concentration of 50 μg/mL, has cytotoxicity and induces cell death, and reduces cell survival by stopping the sub-G1 phase cell cycle. At concentrations of 100-150 μg/mL, fractionation of procaspase-9 and PARP and induction of procaspase-3-8 result. It also suppresses cell cycle protein (cyclin D1) and proteins associated with metastases and angiogenesis of COX-2 and VEGF, and it inhibits nitric oxide synthase and produces COX-2 through low levels of NFkB, as well as ERK and JNK phosphorylation and Suppresses p38.

Scientific name Family name Part of plant Common name Study model The mechanisms of antioxidant and anticancer actions of the most important medicinal plants effective on prostate diseases and prostate cancer
Ref. The compound in this plant is nummularic acid, which is a triterpenoid. 20 μM and 40 μM is anticologenic and antiproliferative, causes apoptosis and induces PARP and partition of caspase 3, also induces phosphorylation of Thr172 in the alpha AMPK subunit and also reduces mTORC1.    Atraric acid is a significant phenolic and sterile compound in this plant that has potent anti-androgenic activity that decreases the proliferation of cancer cells (prostate) and affects androgenic receptors. (60)

Scientific name Family name Part of plant Common name Study model The mechanisms of antioxidant and anticancer actions of the most important medicinal plants effective on prostate diseases and prostate cancer
Ref.
Ocimum tenuiflorum Oleanolic acid, ursolic acid, rosmarinic acid, eugenol, carvacrol, linalool, β-caryophyllene, essential oil, eugenol, β-elemene, β-caryophyllene, germacrene, terpenes.  A variety of vitamins and antioxidant substances also play a significant role in improving prostate function and are used in many natural products to control prostate problems. Anticancer, antioxidant compounds in the diet, such as tocopherols and carotenoids, have been proven in many clinical trials and published. Antioxidants can stimulate the immune system to locate the tumor and destroy its cells or inhibit angiogenesis. It also causes a widespread expression of the p53 gene, which is a suppressor of tumor cells. According to studies, consumption of herbs effective in treating prostate diseases plays an important part in treating the diseases due to fewer side effects and antioxidant and regulator effects. It seems that the herbal products of interest can be effective in controlling the abnormal growth of precancerous lesions and prostate carcinoma (64)(65)(66)(67)(68)(69). Medicinal plants with herbal antioxidants and active ingredients have their effects on the treatment of diseases (70)(71)(72). In this review article, potent biologically active antioxidant compounds from natural sources and medicinal plants with substantial medical and pharmaceutical effects in the treatment of prostate diseases and cancer were discussed. The results of the phytochemical studies have indicated the antioxidant, anticancer and antimicrobial properties of the above-mentioned medicinal plants may be due to biologically active compounds and active flavonoids, such as the active ingredients saponins, lignans, coumarins, phenolic compounds, Dammaranetype saponin, flavones, quercetin, total flavonoids and phenolics, flavan-3-ol, cyanidin-3-glucoside, isoquercitrin, hypoglycin A, 2,6-dimethoxyphenol, syringol, 2-methoxyphenol, baicalin, wogonin, guaiacol, 3,5-dimethoxy-4-hydroxytoluene, norwogonin, oroxylin A, β-sitosterol, quercetin-3-O-β-glucoside, daucosterol, apigenin, luteolin and 2,6-dimethoxy-I,4-benzoquinone. This review highlights some of therapeutic methods and medicinal plants recommended by traditional medicine across the world that have anticancer effect and are effective on prostate diseases and cancer.
The present study sought to introduce the mechanism and the effect of some common herbal drugs with special antioxidant effects, so that they can be used as preventive and therapeutic drug supplements in prostate diseases and tumors in humans. The medicinal plants can also be used to deliver pharmaceutical supplements in medicine due to the presence of antioxidant compounds, biologically active compounds, flavonoids, etc.